Synthesis method of (R)-5-halo-2, 3-dihydro-1H-indene-2-carboxylic acid

Abstract

The invention provides an asymmetric synthesis method of (R)-5-halo-2, 3-dihydro-1H-indene-2-carboxylic acid, and belongs to the technical field of medicine and organic synthesis.

Description

Synthesis method of (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acid Technical Field

[0001] The present invention relates to the fields of medicine and organic synthesis, and in particular to a method for synthesizing a (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acid. Background Art

[0002] Herpesviridae is a family of DNA viruses, including herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), cytomegalovirus (CMV), herpes zoster virus (VZV), Epstein-Barr virus, human herpes virus-6 (HHV6), human herpes virus-7 (HHV7), human herpes virus-8 (HHV8), pseudorabies virus and rhinotracheitis virus. Currently, ganciclovir, acyclovir and foscarnet are used to treat herpes virus infections. However, these treatments have considerable side effects because they damage the replication of host cell DNA or only act on a limited number of viral infections. In addition, known viruses can develop resistance to treatment, resulting in a growing decline in therapeutic efficacy. WO2018 / 127207 reports the synthesis and application of a thiazole compound (WX037), which is a helicase primase inhibitor with strong antiviral effects against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). The compound has advantages such as strong antiviral activity and a new target.

[0003] (R)-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid is a key intermediate in the synthesis compound WX037. In the field of organic synthesis, the preparation of WX037 requires the synthesis of (R)-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid. Therefore, improving the chiral purity and yield of (R)-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid can significantly reduce the production cost of WX037.

[0004] For example, patent CN110225781B discloses a method for synthesizing ethyl 5-bromo-2,3-dihydro-1H-indene-2-carboxylate. The ethyl 5-bromo-2,3-dihydro-1H-indene-2-carboxylate obtained by this synthetic route is a meso compound. First, 4-bromo-1,2-dimethylbenzene and NBS are used as raw materials to undergo a bromination reaction to obtain 4-bromo-1,2-bis(bromomethyl)benzene; 5-bromo-1H-indene-2,2(3H)-dicarboxylate is obtained by ring closure with NaH and diethyl malonate; and then, 5-bromo-2,3-dihydro-1H-indene-2-carboxylate is obtained by decarboxylation with lithium chloride at 160°C. The route is shown below:

[0005] The 5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid ethyl ester intermediate obtained by this method is a meso compound and is not subjected to chiral resolution. Therefore, the crude WX037 racemate obtained when used to prepare WX037 needs to be resolved by SFC to obtain chirally pure WX037, resulting in a high yield and low cost.

[0006] Summary of the Invention

[0007] In order to solve the technical problems faced in the prior art, the present invention aims to provide two methods for synthesizing (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acids with simple post-treatment, high stereoselectivity and relatively high purity, wherein the halogen is, for example, fluorine, chlorine, bromine or iodine. In a first aspect, the present invention provides a method for asymmetric synthesis of (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acids, which does not require SFC splitting and can achieve workshop scale amplification. Specifically, in a first aspect, the present invention provides a method for preparing (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acids, wherein the halogen is, for example, fluorine, chlorine, bromine or iodine, and the method comprises step (a):

[0008] The compound Chiral reduction to compound wherein X is halogen (eg, fluorine, chlorine, bromine or iodine).

[0009] In one embodiment of the first aspect, the chiral reduction in step (a) is hydrogenation with hydrogen in the presence of a chiral catalyst, for example, Ru(OAc)2[s-BINAP].

[0010] In one embodiment of the first aspect, step (a) is carried out in a solvent. For example, the solvent is MeOH, THF, EtOH, IPA, or 2-Me-THF.

[0011] 48, 49, 50, 51, 52, 53, 54, 55°C or a range encompassed by any two of the foregoing values.

[0012] In one embodiment of the first aspect, step (a) further comprises performing chiral resolution after chiral reduction to further improve the compound For example, the chiral resolution is performed using chiral HPLC or a chiral resolving agent. For example, the chiral resolving agent is (S)-phenylethylamine, (R)-phenylethylamine, (R)-1-(1-naphthyl)ethylamine, (S)-1-(1-naphthyl)ethylamine, (R)-(-)-2-amino-1-butanol, (1S,2R)-(-)-1-amino-2-indanol, or cis-1,2-cyclohexanediamine.

[0013] In one embodiment of the first aspect, the method further comprises step (b) before step (a):

[0014] Make compound Reaction with chlorosulfonyl isocyanate to give compound wherein X is halogen (eg, fluorine, chlorine, bromine or iodine).

[0015] In one embodiment of the first aspect, step (b) is carried out in a solvent. For example, the solvent is isopropyl ether, 1,4-dioxane, MTBE, DCM, toluene, THF, acetonitrile, MIBK, Trifluorotoluene, or n-heptane.

[0016] In one embodiment of the first aspect, step (b) is carried out at a temperature of 5-35°C, for example 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35°C or a range encompassed by any two of the above points.

[0017] In one embodiment of the first aspect, the method further comprises step (c) before step (b):

[0018] Make compound Elimination reaction to obtain compound wherein X is halogen (eg, fluorine, chlorine, bromine or iodine).

[0019] In one embodiment of the first aspect, the elimination reaction in step (c) is carried out in the presence of p-toluenesulfonic acid monohydrate, trifluoroacetic acid / methanesulfonyl chloride, or trifluoroacetic acid / triethylsilane.

[0020] In one embodiment of the first aspect, step (c) is carried out in a solvent. For example, the solvent is Toluene, DCM, THF, or TFA.

[0021] In one embodiment of the first aspect, step (c) is carried out at a temperature of 90-120°C, for example 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120°C or a range encompassed by any two of the above points.

[0022] In one embodiment of the first aspect, the method further comprises step (d) before step (c):

[0023] The compound Reduction to compounds wherein X is halogen (eg, fluorine, chlorine, bromine or iodine).

[0024] In one embodiment of the first aspect, the reduction in step (d) is performed using sodium borohydride, lithium borohydride, potassium borohydride, lithium aluminum hydride, or the like.

[0025] In one embodiment of the first aspect, step (d) is carried out in a solvent, for example, ethanol, methanol, isopropanol, or tetrahydrofuran.

[0026] In one embodiment of the first aspect, step (d) is carried out at a temperature of 10-40°C, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40°C or a range encompassed by any two of the above points.

[0027] In a second aspect, the present invention provides a method for asymmetric synthesis of (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acid, which greatly improves stereoselectivity and yield, and has obvious advantages. Specifically, in a second aspect, the present invention provides a method for preparing (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acid, wherein the halogen is, for example, fluorine, chlorine, bromine or iodine, and the method comprises sequentially performing steps (c) and (b) and optionally performing step (a):

[0028] Step (c):

[0029] The compound Chiral reduction to compound wherein X is halogen (e.g., fluorine, chlorine, bromine or iodine), R1 is H or C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl);

[0030] Step (b):

[0031] The compound Reduction to compounds wherein X is halogen (e.g., fluorine, chlorine, bromine or iodine), R1 is H or C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl);

[0032] When R1 is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), step (a) is performed:

[0033] Make compound Hydrolyzed into compounds wherein X is halogen (e.g., fluorine, chlorine, bromine or iodine) and R1 is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl).

[0034] In one embodiment of the second aspect, the chiral reduction in step (c) is carried out in the presence of a chiral catalyst, for example, RuCl(pcymene)[(S,S)-Ts-DPEN], RuCl2[(S)-BINAP], RuBr2[(S)-BINAP], or RuCl[(S,S)-Ts-DPEN](mesitylene).

[0035] In one embodiment of the second aspect, step (c) is performed in the presence of formic acid / triethylamine.

[0036] In one embodiment of the second aspect, step (c) is carried out in a solvent, for example, DCM or THF.

[0037] In one embodiment of the second aspect, step (c) is carried out at a temperature of 10-40°C, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40°C or a range encompassed by any two of the above points.

[0038] In one embodiment of the second aspect, step (b) is carried out in the presence of a reducing agent. For example, the reducing agent is Et3SiH or TMSCl / NaI, preferably Et3SiH. For example, the weight amount of Et3SiH (in grams) relative to the compound The weight dosage (in grams) is 1-10 times, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or the range covered by any two of the above point values, preferably 5, 6, 7, 8, 9, 10 times or the range covered by any two of the above point values.

[0039] In one embodiment of the second aspect, step (b) is carried out in a solvent. For example, the solvent is trifluoroacetic acid, acetonitrile, or tetrahydrofuran. For example, the volume of trifluoroacetic acid used (in milliliters) is about 100 mL relative to the compound. The weight dosage (in grams) is 1-20 times, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or the range covered by any two of the above point values.

[0040] In one embodiment of the second aspect, step (b) is carried out at a temperature of -25 to 5°C, for example -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5°C or a range encompassed by any two of the above points, preferably -10±5°C.

[0041] In one embodiment of the second aspect, the hydrolysis in step (a) is carried out under acidic or alkaline conditions. The conditions are preferably sodium hydroxide / THF / H2O, lithium hydroxide / THF / H2O, CH3SO3H / HCOOH / H2O or concentrated HCl / HCOOH, more preferably concentrated HCl / HCOOH.

[0042] In one embodiment of the second aspect, step (a) is carried out at a temperature of 5-35°C, for example 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35°C or a range encompassed by any two of the above points.

[0043] In one embodiment of the second aspect, the method further comprises step (d) before step (c):

[0044] Make compound With compound Reaction to obtain compound wherein X is halogen (e.g., fluorine, chlorine, bromine or iodine) and R1 is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl).

[0045] In one embodiment of the second aspect, step (d) is carried out in the presence of a base, for example, sodium hydride, lithium bis(trimethylsilyl)amide, n-butyl lithium, or potassium tert-butoxide.

[0046] In one embodiment of the second aspect, step (d) is carried out in a solvent, for example, tetrahydrofuran, dichloromethane, 2-methyltetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide.

[0047] In one embodiment of the second aspect, the compound in step (d) With compound The reaction is carried out at a temperature of 10-40°C, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40°C or a range encompassed by any two of the above points.

[0048] Abbreviations: EtOH, ethanol, TsOH, p-toluenesulfonic acid, MeOH, methanol, Isopropyl ether, MTBE, methyl tert-butyl ether, 1,4-dioxane, 1,4-dioxane, NaCl, sodium chloride, DCM, dichloromethane, NH4Cl, ammonium chloride, Acetonitrile, EA, ethyl acetate, MIBK, methyl tert-butyl ketone, THF, tetrahydrofuran, Trifluorotoluene, Toluene, n-heptane, n-heptane Example

[0049] Example 1

[0050] Step 1: Preparation of compound A2

[0051] Compound A1 (81.8 kg, 388 mol, 1 eq) was dissolved in EtOH (245.4 L, 3 V). NaBH4 (7.33 kg, 194 mol, 0.5 eq) was added portionwise to the mixture at 25±5°C and stirred for 2 hours. The reaction mixture was cooled to 5±5°C and a 20% aqueous NH4Cl solution (245.4 L, 3 V) was added. Extraction was performed with MTBE (409 L x 1, 245.4 L x 1). The organic phase was washed with an 18% aqueous NaCl solution (163.6 L x 2). The organic phase was concentrated under reduced pressure, and toluene (163.6 L, 2 V) was added and concentrated until no fractions remained. Extraction was performed with MTBE (327.2 L x 1), and the mixture was concentrated and replaced with toluene. A brown toluene solution of A2 was obtained with a 14.5% content, 98% purity, and a 97% yield.

[0052] Step 2: Preparation of compound A3

[0053] Compound TsOH.H2O (1.1 kg, 6 mol, 0.01 eq) was dissolved in toluene (295 L, 3.7 V). A toluene solution of A2 (79.76 kg, 374 mol, 1.0 eq) was added dropwise to the mixture at 105±5°C. The mixture was then stirred at 105±5°C for 1 hour. The mixture was cooled to 20-25°C. The layers were separated, and the organic phase was washed with 18% aqueous NaCl solution (159.5 L x 1, then 79.8 L x 1). The organic phase was concentrated under reduced pressure to yield a brown solution of A3 with a 43.2% content, 94.5% purity, and a 94% yield.

[0054] Step 3: Preparation of Compound A5

[0055] Add A3 (156.5 kg, 43.2% assay, 347 mol, 1.0 eq) and isopropyl ether (135.2 kg) in sequence. Then, add chlorosulfonyl isocyanate (73.6 kg, 520 mol, 1.5 eq) dropwise at 20±5°C. Stir at 20±5°C for 40 hours after the addition is complete. Filter under reduced pressure and rinse the filter cake with isopropyl ether (23 kg x 1). Add the filter cake to 1,4-dioxane (209.7 kg, 3.0 V) at 20±5°C, cool to 5±5°C, and add water (33.8 kg, 0.5 V) and 31% concentrated hydrochloric acid (231.2 kg) dropwise. After the addition is complete, heat to 85-90°C and stir for 24 hours. Cool the mixed solution to 25±5°C, add water (270.4 kg, 4.0 V), and stir for 0.5 hour. The mixture was filtered and then washed with water (135.2 kg). The resulting wet cake was stirred with EtOH (202.8 kg) at 20 ± 5 ° C for 1 hour, filtered, and then washed with EtOH (40.56 kg). The resulting wet cake was stirred with MTBE (151.1 kg) at 20 ± 5 ° C for 1 hour, filtered, and then washed with MTBE (50 kg). Vacuum drying gave 37.9 kg of off-white solid A5 with a purity of 95% and a yield of 46%.

[0056] Step 4: Preparation of compound (R)-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid

[0057] Dissolve off-white solid A5 (12 kg, 50 mol, 1.0 eq) in a mixture of MeOH (144 L) and THF (96 L) and replace the atmosphere with nitrogen. Add Ru(OAc)2[s-BINAP] (0.013 eq), replace the atmosphere with hydrogen, and pressurize the mixture to 2.5 MPa. Stir the mixture at 25-40°C for 24 hours. Concentrate the mixture under reduced pressure until no fraction is formed. Add EA (60 L) and continue concentrating until no fraction is formed. Add EA (60 L) and continue concentrating until no fraction is formed. Add EA (120 L) to the mixture, heat to 45-50°C, and dissolve until clear. Add (S)-phenylethylamine dropwise (to a total molar ratio of 1:1 with A5). After the addition is complete, add EA (60 L) to the mixture and stir for 1 hour. Filter and wash the filter cake with EA (24 L). Dissolve the wet filter cake in EA, and heat the mixture to 65±5°C until clear. Stir for 30 minutes. Slowly cool to 25±5°C, stir for 1 hour, filter, and wash the filter cake with EA. Repeat the above steps and crystallize using EA twice to obtain a wet filter cake.

[0058] The wet filter cake was added to EA. The pH was adjusted to 1-3 using 18% aqueous HCl. The liquid phases were separated, and the aqueous phase was extracted with EA. The organic phases were combined and washed three times with water. The organic solution was washed with 10% aqueous NaCl. The organic solution was concentrated under reduced pressure to approximately half the remaining volume. n-heptane was added for crystallization. The mixed solution was filtered and washed with n-heptane. Drying under reduced pressure yielded an off-white solid with a purity of 99.8% and a yield of 38%. Chiral purity was 97.5% with a retention time of 7.24 minutes. 1 H NMR (300MHz, DMSO-d6) δ = 12.33 (s, 1H), 7.41 (s, 1H), 7.30 (d, J = 8.1Hz, 1H), 7.16 (d, J = 8.1Hz, 1H), 3.20 (m, 5H).

[0059] The chiral liquid chromatography conditions for determining the above chiral purity and retention time are as follows:

[0060] Equipment: Agilent 1260 or 1290 HPLC

[0061] Chromatographic column: DAICEL CHIRALPAK AY-3, length 150 mm, inner diameter 3 mm, particle size 4.6 μm

[0062] Mobile phase 1: 0.05% trifluoroacetic acid in water

[0063] Mobile phase 2: 0.05% trifluoroacetic acid in acetonitrile

[0064] Gradient: Time (min) Mobile phase 2 (%)

[0065] 0.0 50

[0066] 12.0 50

[0067] Run time: 12 minutes

[0068] Flow rate: 0.5 ml / min

[0069] Detection wavelength: UV 210 nm

[0070] Injection volume: 1.0 μL

[0071] Example 2

[0072] Where R1 is ethyl

[0073] Step 1: Preparation of compound 1-1B

[0074] To a round-bottom flask, add THF (500 ml, 10 V) and NaH (11.4 g, 473.80 mmol, 2 eq) in sequence. Control the internal temperature at 25 ± 5°C and add a THF (3 V) solution of A1 (50 g, 236.90 mmol, 1 eq) dropwise. Continue to add diethyl carbonate (33.6 g, 1.2 eq) dropwise. Raise the temperature to 60 ± 5°C and react for 2 hours. Cool the reaction solution to 25 ± 5°C and slowly add the reaction solution dropwise to a 1 M hydrochloric acid solution (10 V) at 0-10°C. Extract with ethyl acetate (250 mL × 1), and wash the organic phase with 5% sodium bicarbonate (250 mL × 1). Concentrate the organic phase to 4 V at 40-45°C. Extract the residue with ethyl acetate (250 mL × 1). The organic phase was washed with 5% NaCl (250 mL x 1), dried over anhydrous sodium sulfate for 4 hours, filtered, and rinsed with ethyl acetate (2 V). The filtrate was concentrated at 40-45°C to afford compound 1-1B as a dark green oil with a purity of 83.1% and a yield of 73.4%. LCMS (ESI) m / z: 285.0 (M+1). 1 H NMR (300MHz, CDCl3) δ = 7.38 (m, 2H), 7.28 (d, J = 9.0Hz, 1H), 5.28 (t, J = 6.0Hz, 1H), 4.23 (q, J=6.0Hz, 2H), 3.38 (m, 1H), 3.06 (m, 1H), 1.31 (t, J=6.0Hz, 3H).

[0075] Step 2: Preparation of compound 1-2B

[0076] To a round-bottom flask, dichloromethane (74 mL, 2 V), compound 1-1B (36.9 g, 130.33 mmol, 1 eq), and a mixture of formic acid and triethylamine (0.75 V, formic acid:triethylamine = 5:2) were added sequentially. The atmosphere was purged with nitrogen three times, followed by the addition of RuCl(pcymene)[(S,S)-Ts-DPEN] (4.1 g, 6.52 mmol, 0.05 eq), and the atmosphere was purged with nitrogen three times. Stir at 25±5°C for 16 h. The mixed solution was diluted with dichloromethane (185 mL, 5 V), extracted with water (370 mL, 10 V), and the phases separated. The product remained in the organic phase. The aqueous phase was further extracted with dichloromethane (185 mL x 2), resulting in the product remaining in the organic phase. The combined organic phases were washed with 5% sodium chloride solution (185 mL, 5 V). The organic phase was dried over anhydrous sodium sulfate and separated by column chromatography. 24.8 g of off-white solid compound 1-2B was obtained with a purity of 98.1% and a yield of 66.7%. LCMS (ESI) m / z: 268.0 (M-H2O+1).

[0077] Step 3: Preparation of compound 1-3B

[0078] Where R1 is ethyl

[0079] Under nitrogen, TFA (30 ml, 10 V) and Et3SiH (6.1 g, 52.6 mmol, 5 eq) were added sequentially to a round-bottom flask and stirred at 25±5°C for 10 minutes. The temperature was lowered to -10±5°C, and compound 1-2B (3 g, 10.52 mmol, 1 eq) was added. The mixture was stirred at -10±5°C for 16 hours. The reaction mixture was slowly added to a saturated sodium carbonate solution (30 ml, 10 V) and extracted with dichloromethane (15 ml x 1). The organic phase was dried over anhydrous sodium sulfate for 4 hours. The mixture was filtered and washed with dichloromethane (15 ml). The filtrate was concentrated at 40-45°C to obtain 2.96 g of compound 1-3B as a yellow oil with 100% purity, 100% ee, and a crude yield of 104%. LCMS (ESI) m / z: 270.3 (M+1). 1 H NMR (300MHz, CDCl3) δ = 7.29 (s, 1H), 7.23 (d, J = 9.0Hz, 1H), 7.02 (d, J = 6.0Hz, 1H), 4.14 (q, 2H), 3.27 (m, 1H), 3.15 (m, 4H), 1.25 (t, 3H)

[0080] The reaction conditions of step 3 above are screened as follows:

[0081] (1) Reduction condition screening: Different reducing agents were used to carry out the reaction under the same other conditions. The parameters and results are as follows:

[0082] (2) The effect of reaction temperature on the ratio of impurity elimination was investigated, with other conditions remaining the same. The results showed that the lower the temperature, the higher the reaction selectivity. The optimal reaction selectivity was achieved at -10±5°C, with a ratio of product 1-3B to impurity 1-3B-IMP as high as 99:1. The parameters and results are shown below (where 1-3B-IMP is 5-bromo-1H-indene-2-carboxylic acid):

[0083] (3) Under the same conditions, the effect of triethylsilane equivalent on the impurity elimination ratio was investigated. 2.0 eq, 3.0 eq, 4.0 eq, and 5.0 eq of triethylsilane were tested. The results showed that each condition provided a good intermediate purity and a low impurity elimination ratio. The optimal reaction condition was 5.0 eq of triethylsilane. The parameters and results are shown below (where 1-3B-IMP is 5-bromo-1H-indene-2-carboxylic acid):

[0084] Step 4: Preparation of compound (R)-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid

[0085] Where R1 is ethyl

[0086] Concentrated hydrochloric acid (1 ml, 5 V) and glacial acetic acid (2 ml, 10 V) were added to a round-bottom flask, followed by compound 1-3B (0.2 g, 0.74 mmol, 1 eq). The mixture was heated to 20 ± 5 °C and stirred for 16 hours. Water (2 ml, 10 V) was added dropwise, filtered, and rinsed with water (2 ml). The wet product was dried at 60 ± 5 °C for 16 hours to obtain 0.17 g of light yellow compound A6 with an ee value of 100% and a yield of 95.1%. LCMS (ESI) m / z: 240.9 (M+1). Its hydrogen spectrum data and chiral chromatographic retention time were essentially the same as those of the product in step 4 of Example 1.

[0087] In addition, to avoid racemization during the hydrolysis process and the generation of enantiomeric impurities A6-IMP1, alkaline and acidic hydrolysis conditions were screened separately, all other conditions being the same. The parameters and results are shown below, with the preferred conditions being those used in experimental batches sfl-033, sfl-029, and sfl-043. The preferred hydrolysis conditions were determined to be lithium hydroxide / THF / H2O, or CH3SO3H / HCOOH / H2O, or concentrated HCl / HCOOH, which simultaneously achieved high purity and high enantiomeric excess.

[0088] Example 3

[0089] Where R1 is methyl

[0090] Step 1: Preparation of compound 1-1A

[0091] To a round-bottom flask, add THF (100 ml, 10 V) and NaH (2.3 g, 94.76 mmol, 2 eq) sequentially. Control the internal temperature at 25 ± 5°C and add a solution of A1 (10 g, 47.38 mmol, 1 eq) in THF (30 ml, 3 V) dropwise. Continue adding dimethyl carbonate (5.1 g, 56.86 mmol, 1.2 eq) dropwise. Heat to 60 ± 5°C and react for 2 hours. Cool the reaction mixture to 25 ± 5°C and slowly add 1 M hydrochloric acid solution (100 ml, 10 V) at 0-10°C. Extract with ethyl acetate (50 mL x 1), and wash the organic phase with 5% sodium bicarbonate (50 mL x 1). Concentrate the organic phase to 4 V at 40-45°C. Extract the residue with ethyl acetate (50 mL x 1). The organic phase was washed with 5% NaCl (50 mL x 1), dried over anhydrous sodium sulfate for 4 hours, filtered, and rinsed with ethyl acetate (100 mL, 2 V). The filtrate was concentrated at 40-45°C to yield 7.2 g of ochre-colored solid Compound 1-1A with a purity of 98.3% and a yield of 57%. LCMS (ESI) m / z: 270.0 (M+1).

[0092] Step 2: Preparation of compound 1-2A

[0093] At room temperature (25±5°C), add formic acid (3.85 ml, 0.55 V) to a round-bottom flask. While stirring, control the internal temperature to no more than 35°C. Slowly add triethylamine (1.54 ml, 0.22 V) dropwise. After completion, cool to 25±5°C and set aside. To another round-bottom flask, add dichloromethane (14 ml, 2 V), compound 1-1A (7 g, 26.0 mmol, 1 eq), and a 5:2 mixture of triethylamine formate (5.25 ml, 0.75 V). Replace the atmosphere with nitrogen three times, then add RuCl(pcymene)[(S,S)-Ts-DPEN] (0.82 g, 1.30 mmol, 0.05 eq). Replace the atmosphere with nitrogen again three times. Stir at 25±5°C for 16 h. Add dichloromethane (35 ml, 5 V) and water (35 ml, 10 V), and allow to stand for phase separation. The aqueous phase was back-extracted with dichloromethane (35 ml x 2). The combined organic phases were washed with 5% sodium chloride solution (35 ml, 5 V). The organic phase was dried over anhydrous sodium sulfate for 4 hours, filtered, and rinsed with dichloromethane (14 ml, 2 V). The filtrate was concentrated at 40-45°C, and the residue was separated by column chromatography to obtain 5.5 g of compound 1-2A as a white solid with a purity of 98.5%, an ee of 99.9%, and a yield of 78%. LCMS (ESI) m / z: 254.0 (M-H2O+1).

[0094] Step 3: Preparation of compound 1-3A

[0095] Under nitrogen, TFA (12 ml, 6 V) and Et3SiH (3.4 g, 29.6 mmol, 4 eq) were added sequentially to a round-bottom flask and stirred at 25 ± 5°C for 10 minutes. The temperature was lowered to -10 ± 5°C, and compound 1-2A (2.0 g, 7.4 mmol, 1 eq) was added. The mixture was stirred at -10 ± 5°C for 16 hours. The reaction mixture was slowly added to a saturated sodium carbonate solution (20 ml, 10 V) and extracted with dichloromethane (20 ml x 1). The organic phase was dried over anhydrous sodium sulfate for 4 hours. The mixture was filtered and rinsed with dichloromethane (20 ml). The filtrate was concentrated at 40-45°C to obtain 1.7 g of compound 1-3A as a yellow oil in a 90.4% yield. 1 H NMR (300MHz, CDCl3) δ = 7.32 (s, 1H), 7.26 (d, J = 6.0Hz, 1H), 7.05 (d, J = 6.0Hz, 1H), 3.71 (s, 3H), 3.34 (m, 1H), 3.17 (m, 4H).

[0096] Step 4: Preparation of compound (R)-5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid

[0097] To a round-bottom flask, add concentrated hydrochloric acid (1 ml, 5 V) and glacial acetic acid (2 ml, 10 V), followed by compound 1-3A (0.2 g, 0.74 mmol, 1 eq). Heat to 50 ± 5°C and stir for 16 hours. Cool to 20 ± 5°C, add water (2 ml, 10 V) dropwise, filter, and rinse with water (2 ml). The wet product is dried at 60 ± 5°C for 16 hours to obtain 0.14 g of pale yellow compound A6, in a yield of 74.0%. Its proton spectrum data and chiral chromatographic retention time are essentially the same as those of the product from step 4 of Example 1.

Claims

1. A method for preparing (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acid, comprising step (a): Compound Chiral reduction to compound Wherein X is a halogen.

2. The method of claim 1, wherein step (a) further comprises performing chiral separation after chiral reduction to further improve the compound chiral purity.

3. The method of claim 1 or 2, further comprising step (b) before step (a): Make compound Reaction with chlorosulfonyl isocyanate to give compound Wherein X is a halogen.

4. The method of claim 3, further comprising step (c) before step (b): Make compound Elimination reaction to obtain compound Wherein X is a halogen.

5. The method of claim 4, further comprising step (d) before step (c): Compound Reduction to compounds Wherein X is a halogen.

6. A method for preparing (R)-5-halogen-2,3-dihydro-1H-indene-2-carboxylic acid, comprising sequentially carrying out steps (c) and (b) and optionally carrying out step (a): Step (c): Compound Chiral reduction to compound Wherein X is halogen, R1 is H or C1-C6 alkyl; Step (b): Compound Reduction to compounds Wherein X is halogen, R1 is H or C1-C6 alkyl; When R1 is C1-C6 alkyl, step (a) is performed: Make compound Hydrolyzed into compounds Wherein X is halogen and R1 is C1-C6 alkyl.

7. The method of claim 6, further comprising step (d) before step (c): Make compound With compound Reaction to obtain compound Wherein X is halogen and R1 is C1-C6 alkyl.